The aim of this proposal is to develop aromatase (estrogen synthetase) inhibitors as a new class of compounds that will specifically inhibit estrogen production in vivo. The terminal sequence in the biosynthesis of estrogens involves aromatization of androgen to estrogen. Since this reaction is unique to estrogen biosynthesis, compounds which interact with aromatase may provide a more specific approach and have better properties than those presently available for treating problems associated with reproductive function and for fertility regulation. To date, we have discovered several steroidal compounds with little or no hormonal activity that inhibit in vitro conversion of androgens to estrogen via the aromatase enzyme. They also reduce ovarian estrogen secretion in vivo and prevent ovulation in the rat and hamster. This inhibition can be counteracted by administration of estradiol. They also inhibit or retard implantation in the rat but not in the hamster, a species which does not require estrogen for this process. We plan in this proposal to determine how specific these compounds are for suppressing estrogen, to what extent this occurs at the aromatase level, to what extent anti-LH properties contribute to effectiveness in vivo and whether other enzyme reactions may be inhibited. We also propose to investigate the effects of aromatase inhibitors on the events associated with ovulation and other reproductive processes. We also wish to synthesize better and more potent inhibitors and develop more efficient methods of administration.